Mutation and Genetic Variation

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Mutation and Genetic Variation

• Chapter 4

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Mutation is the ultimate source of genetic
variation

• Point mutations
• base substitutions, insertions, deletions
• Gene duplications
• Changes in chromosome structure
• inversions, translocations
• Changes in chromosome number
• polyploidy

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Estimated number of mutations per genome per
generation (see Table 4.1 of Freeman Herron)
Species Taxonomic group Number of mutant genes per genome per generation
E. coli Bacteria 0.0025
S. cerevisiae Fungi 0.0027
C. elegans Nematode 0.0360
D. melanogaster Insect 0.1400
mouse Mammal 0.9000
human Mammal 1.6000
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More on mutation rates

• Number of mutations per genome per generation is
  a function of
• The number of genes
• The average number of generations of cell
  division that precede gamete production
• The mutation rates on the previous slide are
  underestimates of the total mutation rate because
  they are based only on mutations of large
  effect
• Spontaneous mutation rates may be subject to
  natural selection
• Variation in DNA polymerase affects accuracy of
  replication bacteriophage T4, E. coli
• Efficiency of DNA mismatch repair also under
  genetic control
• Higher mutation rates may confer a selective
  advantage in a novel or changing environment

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Fitness effects of mutations 1

• Fig. 4.6a Effect of mutations on viability in 74
  mutation accumulation lines of Caenorhabditis
  elegans

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Fitness effects of mutations 2

• Fig. 4.6b Effect of large random insertions on
  fitness in E. coli and yeast. The selection
  coefficient is the reduction in growth rate
  (fitness) of mutant cells relative to non-mutated
  controls

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Fitness effects of mutations summary

• Most mutations are slightly deleterious or
  neutral
• Few mutations are beneficial
• New mutations will be heterozygous in diploids
  therefore, recessive mutations (even good ones)
  will have no immediate phenotypic effect and will
  not be subjected to natural selection (while
  heterozygous)

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Population size, mutation and natural selection

• Larger populations will have more new mutant
  alleles of each gene in each generation
• If humans, on average, have 1.6 new mutations per
  genome per generation and have 25,000 genes, then
  there will be 1 new mutant allele per gene per
  (25,000/1.6) 15,600 people in each generation
  (100 new mutant alleles per gene per generation
  in a population of 1.56 million)
• This calculation suggests that natural selection
  will be most effective at producing adaptive
  evolution in large populations because larger
  populations harbor more genetic variation, which
  is the raw material that underlies the
  phenotypic variation upon which natural selection
  acts.

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Where new genes come from gene duplication

• Duplicate genes can be created by unequal
  crossing over
• Duplicated genes can form gene families and
  superfamilies
• Duplicate genes can
• Remain the same 45s rRNA genes (increase
  dosage)
• Differentiate, but continue to perform similar
  functions globins (oxygen transport)
• Perform unrelated functions crystallins and
  their ancestors
• Become junk pseudogenes

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Fig. 4.7 Unequal Cross-over and the origin of
gene duplications
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The globin superfamily in humans

• The a-globin family
• Chromosome 16
• contains (in order) z, yz, ya2, ya1, a2, a1, q
• The b-globin family
• chromosome 11
• contains (in order) e, Gg, Ag, yb1, d, b
• Myoglobin
• chromosome 22
• found in muscles
• Globin myoglobin duplication gt800 Myr
• Split between a- and b-globin families 450 500
  Myr (a- and b-globin about 46 amino acid
  sequence similarity)

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Fig. 4.8 Developmental expression members of
globin gene family
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Fig. 4.9 Tran-scription units in the globin gene
family
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Some Gene Families

• Actins 5-30
• Myosin (heavy chain) 5-10
• Histones 100-1,000
• 45s rRNA (human) gt 300 (5 chromosomes)
• Keratins gt 20
• Globins (a-like) 1-5
• Globins (b-like) 50

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Fig. 4.10 Chromosome inversion
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Characteristics of Inversions

• Do not generally create new alleles (or genes)
• Suppress crossing over when an inversion is
  heterozygous with a normal chromosome
• i.e., recombination is prevented or reduced among
  the group of genes included within an inversion,
  so those genes act as a block or supergene,
  which may be adaptive
• Occur in many, if not all, organisms, but are
  particularly well-known in Drosophila (D.
  pseudoobscura, D. subobscura)

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Fig. 4.11 Inversion frequency clines in D.
subobscura
Frequency of the Est inversion
South America North
America
South latitude North
latitude
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Polyploidy

• Polyploid means having 3 or more complete haploid
  chromosome sets
• e.g. Mendels peas were diploid and had 2n 14
  chromosomes (each haploid set had n 7
  chromosomes). A triploid pea would have 3n 21
  chromosomes, and a tetraploid pea would have 4n
  28 chromosomes
• Polyploidy is common in higher plants, much rarer
  in animals
• More than one-half of angiosperms are polyploid
  (relative to ancestors with fewer sets of
  chromosomes)

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Fig. 4.12 Origin of tetraploidy in plants
Cell-division error causes production of diploid
gametes
Parent
1st generation offspring
Selfs, mates with 4n sibling, Or backcrosses to
parent
2nd generation offspring
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Frequency of Polyploidy

• Some studies suggest that flowering plant species
  typically produce diploid gametes at a frequency
  of 0.00465
• The probability of two diploid gametes meeting to
  produce a zygote is, then, (0.00465)2 2.16 x
  10-5 (or about 2 out of every 100,000 offspring
  are tetraploid)

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Importance of Polyploidy

• Duplicates all genes, which may evolve new
  functions
• A tetraploid, for example, is reproductively
  isolated from its diploid parent because the
  hybrid is triploid and sterile. Thus, the
  tetraploid is, in effect, a new species
• Triploids have commercial significance because
  they are seedless

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Ploidy in three species of Iris

• Iris setosa has 2n 36 chromosomes (n18)
• Iris virginica has 72 chromosomes (4n)
• Iris versicolor has 108 chromosomes (6n)
• I. Versicolor (common blue flag) may have been
  derived by hybridization between the other two
  species
• Proportion of polyploid angiosperms is estimated
  to be from 30 (Stebbins 1950) to 50-70 (Stace
  1989)

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How much genetic variation is there? 1

• Table 4.4 of your text gives the genotypes at the
  CCR5 gene in samples from various human
  populations (CCR5 protein is the co-receptor that
  HIV uses to enter host cells)
• For example, the sample of 102 people from
  Iceland is as follows
• Genotype / /D32 D32/D32
• Number in sample 75 24 3

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How much genetic variation is there? 2

• Iceland sample (N 102)
• Genotype / /D32 D32/D32
• Number in sample 75 24 3
• The frequency of the allele is
• (75 x 2) 24 / (102 x 2) 0.853
• The frequency of the D32 allele is
• (3 x 2) 24 / (102 x 2) 0.147
• The heterozygosity of this sample is
• 24/102 0.235

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How much genetic variation is there? Variation
in allele frequencies among populations

• Frequency of alcohol dehydrogenase (Adh) alleles
  in Australian fruit fly populations
• Geograpic pattern may result from greater
  stability of the AdhS allele at higher
  temperatures

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How much genetic variation is there?
Heterozygosity

• Heterozygosity is a commonly used measure of
  genetic variation for conventional genes, such as
  enzyme-coding loci
• Heterozygosity increases with the number of
  alleles at a locus and is greatest when all
  alleles have the same frequency
• 1 allele (a monomorphic locus) HHW 0
• 2 alleles with frequencies 0.9 and 0.1 HHW
  2(0.9)(0.1) 0.18
• 2 alleles with frequencies 0.5 HHW 2(0.5)(0.5)
  0.50
• 4 alleles with frequencies 0.25 HHW 1 -
  4(0.25)2 0.75
• Where HHW is the expected heterozygosity when
  genotypes are in Hardy-Weinberg proportions

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Fig. 4.16 Heterozy-gosityenzyme loci
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How much genetic variation is there? 3

• Enzyme loci
• 1/3 to 1/2 of genes are polymorphic in a typical
  population that is they have 2 or more alleles
  with a frequency gt 1 (or 5)
• a typical individual will be heterozygous at 4
  15 of its loci
• variation at enzyme loci is generally assayed by
  gel electrophoresis, which will detect only amino
  acid sequence differences in the gene products
• We see even more variation when we look directly
  at nucleotide sequences of genes synonymous
  substitutions, substitutions in non-translated
  regions

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Fig. 4.17 Loss-of-function mutations in a sample
of 30,000 disease-causing alleles of the cystic
fibrosis gene